tbuckley/cabot-search huggingface dataset:
Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial
Authors: Sanne A.L. Bartels, Mila Donker, Coralie Poncet, Nicolas Sauvé, Marieke E. Straver, Cornelis J.H. van de Velde, Robert E. Mansel, Charlotte Blanken, Lorenzo Orzalesi, Jean H.G. Klinkenbijl, Huub C.J. van der Mijle, Grard A.P. Nieuwenhuijzen, Sanne C. Veltkamp, Thijs van Dalen, Andreas Marinelli, Herman Rijna, Marko Snoj, Nigel J. Bundred, Jos W.S. Merkus, Yazid Belkacemi, Patrick Petignat, Dominic A.X. Schinagl, Corneel Coens, Geertjan van Tienhoven, Frederieke van Duijnhoven, Emiel J.T. Rutgers
Journal: Journal of Clinical Oncology (2022)

The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life.In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681).Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND.This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.
Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension
Authors: Weibin Zhou, Keli Liu, Lei Zeng, Jiaqi He, Xinbo Gao, Xinyu Gu, Xun Chen, Jing Jing Li, Minghui Wang, Duoguang Wu, Zhixiong Cai, Lena Claesson-Welsh, Rong Ju, Jingfeng Wang, Feng Zhang, Yangxin Chen
Journal: Circulation (2022)

Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear.VEGF-A/VEGFR2 signal activation and VEGFR2 Y949-dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure.We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH.Our results support the notion that VEGF-A/VEGFR2 Y949-dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.
<i>KIT</i>D816V mutation in blood for the diagnostic screening of systemic mastocytosis and mast cell activation syndromes
Authors: Paula Navarro‐Navarro, Iván Álvarez‐Twose, Alba Pérez‐Pons, Ana Henriques, Andrea Mayado, Andrés C. García‐Montero, Laura Sánchez‐Muñoz, Oscar González‐López, Almudena Matito, Carolina Caldas, María Jara‐Acevedo, Alberto Orfao
Journal: Allergy (2022)

Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations.Here, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood-purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow-up and its association with disease outcome.Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V-mutated cells in blood (P = .0004) and a high rate of discordant BM+ /blood- samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well-differentiated variants of indolent SM (7%). Purification of different compartments of blood-derived myeloid cells was done in 28 patients who were BM mast cell (MC)+ /blood- for KITD816V, revealing KITD816V-mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V-mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression-free survival (PFS).These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood-purified myeloid cell populations.
International Society for Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of cutaneous T-cell lymphoma outcomes during the COVID-19 pandemic: A retrospective cohort study
Authors: Larisa J. Geskin, Bradley D. Kwinta, Tiffany J. Garcia-Saleem, Oleg E. Akilov, Paula A. Enz, Emmanuella Guenova, Pablo L. Ortiz-Romero, Evangelia Papadavid, Pietro Quaglino, Sima Rozati, Connor J. Stonesifer, Austin Burns, William S. Stringer, Eloy Tarin, Julia J. Scarisbrick
Journal: Journal of the American Academy of Dermatology (2022)
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Journal: JAMA Network Open (2022)

Filippo Cacioppo, MD; Denise Reisenbauer, BSc; Harald Herkner, MSc, MD; Julia Oppenauer, MD; Nikola Schuetz, MD; Jan Niederdoeckl, MD, PhD; Sebastian Schnaubelt, MD, PhD; Sophie Gupta, MD; Martin Lutnik, MD; Alexander Simon, MD; Alexander O. Spiel, MD; Nina Buchtele, MD, PhD; Hans Domanovits, MD; Anton N. Laggner, MD; Michael Schwameis, MD
Questionnaire-Based Polyexposure Assessment Outperforms Polygenic Scores for Classification of Type 2 Diabetes in a Multiancestry Cohort
Authors: Farida S. Akhtari, Dillon Lloyd, Adam Burkholder, Xiaoran Tong, John S. House, Eunice Y. Lee, John Buse, Shepherd H. Schurman, David C. Fargo, Charles P. Schmitt, Janet Hall, Alison A. Motsinger-Reif
Journal: Diabetes Care (2022)

OBJECTIVE Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes. RESEARCH DESIGN AND METHODS Using logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hypertension, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of 13 environmental variables. Using UK Biobank data, we developed a multiancestry PGS and calculated it for participants. RESULTS We found 76 significant associations with type 2 diabetes, including novel associations of asbestos and coal dust exposure. OCS, PXS, and PGS were significantly associated with type 2 diabetes. PXS had moderate power to determine associations, with larger effect size and greater power and reclassification improvement than PGS. For all scores, the results differed by race. CONCLUSIONS Our findings in a multiancestry cohort elucidate how type 2 diabetes odds can be attributed to clinical, genetic, and environmental factors and emphasize the need for exposome data in disease-risk association studies. Race-based differences in predictive scores highlight the need for genetic and exposome-wide studies in diverse populations.
Molecularly Defined Subsets of Ewing Sarcoma Tumors Differ in Their Responses to IGF1R and WEE1 Inhibition
Authors: Upendra Kumar Soni, Yuhua Wang, Ram Naresh Pandey, Ryan Roberts, Joseph G. Pressey, Rashmi S. Hegde
Journal: Clinical Cancer Research (2022)

Targeted cancer therapeutics have not significantly benefited patients with Ewing sarcoma with metastatic or relapsed disease. Understanding the molecular underpinnings of drug resistance can lead to biomarker-driven treatment selection.Receptor tyrosine kinase (RTK) pathway activation was analyzed in tumor cells derived from a panel of Ewing sarcoma tumors, including primary and metastatic tumors from the same patient. Phospho-RTK arrays, Western blots, and IHC were used. Protein localization and the levels of key markers were determined using immunofluorescence. DNA damage tolerance was measured through PCNA ubiquitination levels and the DNA fiber assay. Effects of pharmacologic inhibition were assessed in vitro and key results validated in vivo using patient-derived xenografts.Ewing sarcoma tumors fell into two groups. In one, IGF1R was predominantly nuclear (nIGF1R), DNA damage tolerance pathway was upregulated, and cells had low replication stress and RRM2B levels and high levels of WEE1 and RAD21. These tumors were relatively insensitive to IGF1R inhibition. The second group had high replication stress and RRM2B, low levels of WEE1 and RAD21, membrane-associated IGF1R (mIGF1R) signaling, and sensitivity to IGF1R or WEE1-targeted inhibitors. Moreover, the matched primary and metastatic tumors differed in IGF1R localization, levels of replication stress, and inhibitor sensitivity. In all instances, combined IGF1R and WEE1 inhibition led to tumor regression.IGF1R signaling mechanisms and replication stress levels can vary among Ewing sarcoma tumors (including in the same patient), influencing the effects of IGF1R and WEE1 treatment. These findings make the case for using biopsy-derived predictive biomarkers at multiple stages of Ewing sarcoma disease management.
RAGE ablation attenuates glioma progression and enhances tumor immune responses by suppressing galectin-3 expression
Authors: Ian Y Zhang, Shunan Liu, Leying Zhang, Rongrui Liang, Qingxiao Fang, Jie Zhao, Lyuzhi Ren, Eric F Medina, Aleksandr Filippov, Kimberley-Jane Bonjoc, Ammar Chaudhry, Mojtaba Dayyani, Andrea H Bild, Behnam Badie
Journal: Neuro-Oncology (2022)

Malignant gliomas consist of heterogeneous cellular components that have adopted multiple overlapping escape mechanisms that overcome both targeted and immune-based therapies. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that is activated by diverse proinflammatory ligands present in the tumor microenvironment. Activation of RAGE by its ligands stimulates multiple signaling pathways that are important in tumor growth and invasion. However, treatment strategies that only target the interaction of RAGE with its ligands are ineffective as cancer therapies due to the abundance and diversity of exogenous RAGE ligands in gliomas.As an alternative approach to RAGE ligand inhibition, we evaluated the genetic ablation of RAGE on the tumorigenicity of 2 syngeneic murine glioma models. RAGE expression was inhibited in the GL261 and K-Luc gliomas by shRNA and CRSPR/Cas9 techniques prior to intracranial implantation. Tumor growth, invasion, and inflammatory responses were examined by histology, survival, Nanostring, and flow cytometry.Intracellular RAGE ablation abrogated glioma growth and invasion by suppressing AKT and ERK1/2 activities and by downregulating MMP9 expression. Interestingly, RAGE inhibition in both glioma models enhanced tumor inflammatory responses by downregulating the expression of galectin-3 and potentiated immunotherapy responses to immune checkpoint blockade.We demonstrated that intracellular RAGE ablation suppresses multiple cellular pathways that are important in glioma progression, invasion, and immune escape. These findings strongly support the development of RAGE ablation as a treatment strategy for malignant gliomas.
Association between Short-Term Exposure to Air Pollution and COVID-19 Mortality: A Population-Based Case-Crossover Study Using Individual-Level Mortality Registry Confirmed by Medical Examiners
Authors: Honghyok Kim, Jonathan M. Samet, Michelle L. Bell
Journal: Environmental Health Perspectives (2022)

Background: Studies have suggested links between ambient air pollution and coronavirus 2019 (COVID-19) mortality, yet confirmation by well-designed epidemiological studies with individual data is needed. Objectives: We aimed to examine whether short-term exposure to air pollution is associated with risk of mortality from COVID-19 for those infected with COVID-19. Methods: The Cook County Medical Examiner's Office reports individual-level data for deaths from COVID-19 that occur in its jurisdiction, which includes all confirmed COVID-19 deaths in Cook County, Illinois. Case-crossover analysis was conducted to estimate the associations of estimated short-term exposures to particulate matter (PM) with aerodynamic diameter ≤2.5μm (PM2.5) and ozone (O3) on the day of death and up to 21 d before death at location of death with COVID-19. A total of 7,462 deaths from COVID-19 that occurred up to 28 February 2021 were included in the final analysis. We adjusted for potential confounders by time-stratified case-crossover design and by covariate adjustments (i.e., time-invariant factors, meteorological factors, viral transmission, seasonality, and time trend). Results: Of the 7,462 case and 25,457 self-control days, almost all were days with exposure levels below the PM2.5 24-h National Ambient Air Quality Standard (NAAQS) (35 μg/m3); 98.9% had O3 levels below the maximum 8-h NAAQS (35.7 μg/m3 or 70 parts per billion). An interquartile range (IQR) increase (5.2 μg/m3) in cumulative 3-wk PM2.5 exposure was associated with a 69.6% [95% confidence interval (CI): 34.6, 113.8] increase in risk of COVID-19 mortality. An IQR increase (8.2 μg/m3) in 3-d O3 exposure was associated with a 29.0% (95% CI: 9.9, 51.5) increase in risk of COVID-19 mortality. The associations differed by demographics or race/ethnicity. There was indication of modification of the associations by some comorbid conditions. Discussion: Short-term exposure to air pollution below the NAAQS may increase the mortality burden from COVID-19. https://doi.org/10.1289/EHP10836
Anti‐KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria
Authors: Dorothea Terhorst‐Molawi, Tomasz Hawro, Eva Grekowitz, Lea Kiefer, Kunal Merchant, Diego Alvarado, Lawrence J. Thomas, Thomas Hawthorne, Elizabeth Crowley, Margo Heath‐Chiozzi, Martin Metz, Marcus Maurer
Journal: Allergy (2022)

Abstract Background Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)‐mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX‐0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose‐dependent plasma tryptase suppression indicative of systemic mast cell ablation. Methods This is an open‐label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12‐week follow‐up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI). Results Analysis populations were safety ( n = 21) and pharmacodynamics/clinical activity ( n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (&lt;limit of detection), and increased soluble SCF through Week 12. Complete responses (negative provocation test) occurred in 95% ( n = 19/20) of patients ( n = 10/10 ColdU; n = 9/10 SD), and all ( n = 20/20) showed improvement in urticaria control (UCT ≥ 12). The kinetics of clinical activity mirrored that of MC and tryptase reduction. DLQI‐measured impairment significantly decreased to minimal/none in 93% of patients on study. Conclusion In CIndU patients, barzolvolimab was well tolerated, demonstrated marked, rapid, durable depletion of skin MCs, circulating tryptase, and reductions in clinical activity with significant improvements in disease control and quality of life (QoL) demonstrating potential therapeutic effects for MC‐mediated disorders.
Functional Blood–Brain Barrier Model with Tight Connected Minitissue by Liquid Substrates Culture
Authors: Nian Liu, Yuanbo Zhu, Kang Yu, Zeming Gu, Shang Lv, Yuewei Chen, Chaofan He, Jianzhong Fu, Yong He
Journal: Advanced Healthcare Materials (2022)

The functional blood-brain barrier (BBB) model can provide a reliable tool for better understanding BBB transport mechanisms and in vitro preclinical experimentation. However, recapitulating microenvironmental complexities and physiological functions in an accessible approach remains a major challenge. Here, a new BBB model with a high-cell spatial density and tightly connected biomimetic minitissue is presented. The minitissue, pivotal functional structure of the BBB model, is fabricated by a novel and easy-to-use liquid substrate culture (LSC) method, which allows cells to self-assemble and self-heal into macrosized, tightly connected membranous minitissue. The minitissue with uniform thickness can be easily harvested in their entirety with extracellular matrix. Attributed to the tightly connected minitissue formed by LSC, the fabricated BBB biomimetic model has 1 to 2 orders of magnitude higher transendothelial electric resistance than the commonly reported BBB model. It also better prevents the transmission of large molecular substances, recapitulating the functional features of BBB. Furthermore, the BBB biomimetic model provides feedback regarding BBB-destructive drugs, exhibits selective transmission, and shows efflux pump activity. Overall, this model can serve as an accessible tool for life science or clinical medical researchers to enhance the understanding of human BBB and expedite the development of new brain-permeable drugs.
IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network
Authors: Niklas A. Schmacke, Fionan O’Duill, Moritz M. Gaidt, Inga Szymanska, Julia M. Kamper, Jonathan L. Schmid-Burgk, Sophia C. Mädler, Timur Mackens-Kiani, Tatsuya Kozaki, Dhruv Chauhan, Dennis Nagl, Che A. Stafford, Hartmann Harz, Adrian L. Fröhlich, Francesca Pinci, Florent Ginhoux, Roland Beckmann, Matthias Mann, Heinrich Leonhardt, Veit Hornung
Journal: Immunity (2022)
A Review of Recent Progress on Collagen‐Based Biomaterials
Authors: Manhui Zheng, Xuechuan Wang, Yining Chen, Ouyang Yue, Zhongxue Bai, Boqiang Cui, Huie Jiang, Xinhua Liu
Journal: Advanced Healthcare Materials (2022)

Abstract Since the 2010s, the demand for healthcare models has exceeded the prevailing resources available due to the rapid increase in the aging population in China. However, a significant gap in development of biomedical materials remains, especially between China and the western developed countries. Collagen is the major protein of the extracellular matrix (ECM) and has been extensively applied in medical fields. Collagen‐based biomaterials (CBBs) are used to prepare dressings and dermal substitutes, surgical sutures, plasma substitutes, tissue‐engineered scaffolds, and drug delivery systems; this is attributed to their exceptional biocompatibility, biodegradability, hypoimmunogenicity, and coordination between collagen hosts and tissues. This review provides thorough strides in CBB structures, crosslinking and forming technologies, and real‐world applications. First, the natural origin and specific structures of animal‐derived collagen and non‐animal‐derived collagen are introduced and compared. Second, crosslinking methods and forming technologies of CBBs across the board are discussed. Third, several examples are considered to demonstrate the practical biomedical use of CBBs and highlight cautionary notes. Finally, the underlying development directions of CBBs from an interdisciplinary perspective are outlined. This review aims to provide comprehensive mechanisms by which collagen can be uniquely and practically used as advanced biomaterial, hence providing options for augmenting its development in China.